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Zhang PP, Li L, Qu HY, Chen GY, Xie MZ, Chen YK. Traditional Chinese medicine in the treatment of Helicobacter pylori-related gastritis: The mechanisms of signalling pathway regulations. World J Gastroenterol 2025; 31:96582. [PMID: 39839895 PMCID: PMC11684169 DOI: 10.3748/wjg.v31.i3.96582] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/10/2024] [Revised: 09/29/2024] [Accepted: 12/02/2024] [Indexed: 12/20/2024] Open
Abstract
Helicobacter pylori-associated gastritis (HPAG) is a common condition of the gastrointestinal tract. However, extensive and long-term antibiotic use has resulted in numerous adverse effects, including increased resistance, gastrointestinal dysfunction, and increased recurrence rates. When these concerns develop, traditional Chinese medicine (TCM) may have advantages. TCM is based on the concept of completeness and aims to eliminate pathogens and strengthen the body. It has the potential to prevent this condition while also boosting the rate of Helicobacter pylori eradication. This review elaborates on the mechanism of TCM treatment for HPAG based on cellular signalling pathways, which reflects the flexibility of TCM in treating diseases and the advantages of multi-level, multi-pathway, and multi-target treatments for HPAG.
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Affiliation(s)
- Pei-Pei Zhang
- School of Traditional Chinese Medicine, Hunan University of Chinese Medicine, Changsha 410200, Hunan Province, China
- Hunan Engineering Technology Research Center for Medicinal and Functional Food, Hunan University of Chinese Medicine, Changsha 410200, Hunan Province, China
- Key Laboratory of Traditional Chinese Medicine Heart and Lung Syndrome Differentiation and Medicated Diet and Dietotherapy, Hunan University of Chinese Medicine, Changsha 410200, Hunan Province, China
| | - Liang Li
- School of Traditional Chinese Medicine, Hunan University of Chinese Medicine, Changsha 410200, Hunan Province, China
- Hunan Engineering Technology Research Center for Medicinal and Functional Food, Hunan University of Chinese Medicine, Changsha 410200, Hunan Province, China
- Key Laboratory of Traditional Chinese Medicine Heart and Lung Syndrome Differentiation and Medicated Diet and Dietotherapy, Hunan University of Chinese Medicine, Changsha 410200, Hunan Province, China
| | - Hao-Yu Qu
- Hunan Engineering Technology Research Center for Medicinal and Functional Food, Hunan University of Chinese Medicine, Changsha 410200, Hunan Province, China
- School of Informatics, Hunan University of Chinese Medicine, Changsha 410208, Hunan Province, China
| | - Guang-Yu Chen
- School of Traditional Chinese Medicine, Hunan University of Chinese Medicine, Changsha 410200, Hunan Province, China
- Hunan Engineering Technology Research Center for Medicinal and Functional Food, Hunan University of Chinese Medicine, Changsha 410200, Hunan Province, China
- Key Laboratory of Traditional Chinese Medicine Heart and Lung Syndrome Differentiation and Medicated Diet and Dietotherapy, Hunan University of Chinese Medicine, Changsha 410200, Hunan Province, China
| | - Meng-Zhou Xie
- School of Traditional Chinese Medicine, Hunan University of Chinese Medicine, Changsha 410200, Hunan Province, China
- Hunan Engineering Technology Research Center for Medicinal and Functional Food, Hunan University of Chinese Medicine, Changsha 410200, Hunan Province, China
- Key Laboratory of Traditional Chinese Medicine Heart and Lung Syndrome Differentiation and Medicated Diet and Dietotherapy, Hunan University of Chinese Medicine, Changsha 410200, Hunan Province, China
| | - Yan-Kun Chen
- School of Traditional Chinese Medicine, Hunan University of Chinese Medicine, Changsha 410200, Hunan Province, China
- Precision Medicine Research and Development Center, Zhuhai Institute of Advanced Technology, Chinese Academy of Sciences, Zhuhai 519000, Guangdong Province, China
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Old and New Aspects of H. pylori-Associated Inflammation and Gastric Cancer. CHILDREN 2022; 9:children9071083. [PMID: 35884067 PMCID: PMC9322908 DOI: 10.3390/children9071083] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 06/19/2022] [Revised: 07/17/2022] [Accepted: 07/18/2022] [Indexed: 12/16/2022]
Abstract
H. pylori is involved in the development of 80% of gastric cancers and 5.5% of all malignant conditions worldwide. Its persistence within the host’s stomach causes chronic inflammation, which is a well-known hallmark of carcinogenesis. A wide range of cytokines was reported to be involved in the initiation and long-term persistence of this local and systemic inflammation. IL-8 was among the first cytokines described to be increased in patients with H. pylori infection. Although, this cytokine was initially identified to exert a chemoattracting effect that represents a trigger for the activation of inflammatory cells within H.-pylori-infected mucosa, more recent studies failed in encountering any association between IL-8 and H. pylori infection. IL-6 is a multifunctional, pleiotropic and multipotent cytokine involved in mediating the interaction between innate and adaptive immunity with a dichotomous role acting as both a proinflammatory and an anti-inflammatory cytokine depending on the signaling pathway. IL-1α functions as a promoter of angiogenesis and vascular endothelial cell proliferation in gastric carcinoma since it is closely related to H.-pylori-induced inflammation in children. IL-1β is an essential trigger and enhancer of inflammation. The association between a low IL-1β level and an increased TNF-α level might be considered a risk factor for peptic ulcer disease in the setting of H. pylori infection. IL-10 downregulates both cytotoxic inflammatory responses and cell-mediated immune responses. H. pylori uses the immunosuppressive role of IL-10 to favor its escape from the host’s immune system. TGFβ is a continuous inflammatory mediator that promotes the adherence of H. pylori to the host’s cells and their subsequent colonization. The role of H.-pylori-induced inflammatory responses in the onset of gastric carcinogenesis seems to represent the missing puzzle piece for designing effective preventive and therapeutic strategies in patients with H.-pylori-associated gastric cancer.
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Yin H, Guo R, Zhang H, Liu S, Gong Y, Yuan Y. A Dynamic Transcriptome Map of Different Tissue Microenvironment Cells Identified During Gastric Cancer Development Using Single-Cell RNA Sequencing. Front Immunol 2021; 12:728169. [PMID: 34745098 PMCID: PMC8566821 DOI: 10.3389/fimmu.2021.728169] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2021] [Accepted: 10/06/2021] [Indexed: 12/20/2022] Open
Abstract
Gastric cancer (GC) development trends have identified multiple processes ranging from inflammation to carcinogenesis, however, key pathogenic mechanisms remain unclear. Tissue microenvironment (TME) cells are critical for the progression of malignant tumors. Here, we generated a dynamic transcriptome map of various TME cells during multi-disease stages using single-cell sequencing analysis. We observed a set of key transition markers related to TME cell carcinogenic evolution, and delineated landmark dynamic carcinogenic trajectories of these cells. Of these, macrophages, fibroblasts, and endothelial cells exerted considerable effects toward epithelial cells, suggesting these cells may be key TME factors promoting GC occurrence and development. Our results suggest a phenotypic convergence of different TME cell types toward tumor formation processes in GC. We believe our data would pave the way for early GC detection, diagnosis, and treatment therapies.
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Affiliation(s)
- Honghao Yin
- Tumor Etiology and Screening Department of Cancer Institute and General Surgery, The First Hospital of China Medical University, Shenyang, China.,Key Laboratory of Cancer Etiology and Prevention in Liaoning Education Department, The First Hospital of China Medical University, Shenyang, China.,Key Laboratory of GI Cancer Etiology and Prevention in Liaoning Province, The First Hospital of China Medical University, Shenyang, China
| | - Rui Guo
- Tumor Etiology and Screening Department of Cancer Institute and General Surgery, The First Hospital of China Medical University, Shenyang, China.,Key Laboratory of Cancer Etiology and Prevention in Liaoning Education Department, The First Hospital of China Medical University, Shenyang, China.,Key Laboratory of GI Cancer Etiology and Prevention in Liaoning Province, The First Hospital of China Medical University, Shenyang, China
| | - Huanyu Zhang
- Tumor Etiology and Screening Department of Cancer Institute and General Surgery, The First Hospital of China Medical University, Shenyang, China.,Key Laboratory of Cancer Etiology and Prevention in Liaoning Education Department, The First Hospital of China Medical University, Shenyang, China.,Key Laboratory of GI Cancer Etiology and Prevention in Liaoning Province, The First Hospital of China Medical University, Shenyang, China
| | - Songyi Liu
- Tumor Etiology and Screening Department of Cancer Institute and General Surgery, The First Hospital of China Medical University, Shenyang, China.,Key Laboratory of Cancer Etiology and Prevention in Liaoning Education Department, The First Hospital of China Medical University, Shenyang, China.,Key Laboratory of GI Cancer Etiology and Prevention in Liaoning Province, The First Hospital of China Medical University, Shenyang, China
| | - Yuehua Gong
- Tumor Etiology and Screening Department of Cancer Institute and General Surgery, The First Hospital of China Medical University, Shenyang, China.,Key Laboratory of Cancer Etiology and Prevention in Liaoning Education Department, The First Hospital of China Medical University, Shenyang, China.,Key Laboratory of GI Cancer Etiology and Prevention in Liaoning Province, The First Hospital of China Medical University, Shenyang, China
| | - Yuan Yuan
- Tumor Etiology and Screening Department of Cancer Institute and General Surgery, The First Hospital of China Medical University, Shenyang, China.,Key Laboratory of Cancer Etiology and Prevention in Liaoning Education Department, The First Hospital of China Medical University, Shenyang, China.,Key Laboratory of GI Cancer Etiology and Prevention in Liaoning Province, The First Hospital of China Medical University, Shenyang, China
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Rakhimova O, Schmidt A, Landström M, Johansson A, Kelk P, Romani Vestman N. Cytokine Secretion, Viability, and Real-Time Proliferation of Apical-Papilla Stem Cells Upon Exposure to Oral Bacteria. Front Cell Infect Microbiol 2021; 10:620801. [PMID: 33718256 PMCID: PMC7945949 DOI: 10.3389/fcimb.2020.620801] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2020] [Accepted: 12/31/2020] [Indexed: 01/09/2023] Open
Abstract
The use of stem cells from the apical papilla (SCAPs) has been proposed as a means of promoting root maturation in permanent immature teeth, and plays a significant role in regenerative dental procedures. However, the role of SCAPs may be compromised by microenvironmental factors, such as hypoxic conditions and the presence of bacteria from infected dental root canals. We aim to investigate oral bacterial modulation of SCAP in terms of binding capacity using flow cytometry and imaging, real-time cell proliferation monitoring, and cytokine secretion (IL-6, IL-8, and TGF-β isoforms) under anaerobic conditions. SCAPs were exposed to key species in dental root canal infection, namely Actinomyces gerensceriae, Slackia exigua, Fusobacterium nucleatum, and Enterococcus faecalis, as well as two probiotic strains, Lactobacillus gasseri strain B6 and Lactobacillus reuteri (DSM 17938). We found that A. gerensceriae, S. exigua, F. nucleatum, and E. faecalis, but not the Lactobacillus probiotic strains bind to SCAPs on anaerobic conditions. Enterococcus faecalis and F. nucleatum exhibited the strongest binding capacity, resulting in significantly reduced SCAP proliferation. Notably, F. nucleatum, but not E. faecalis, induce production of the proinflammatory chemokine IL-8 and IL-10 from SCAPs. Production of TGF-β1 and TGF-β2 by SCAPs was dependent on species, cell line, and time, but secretion of TGF-β3 did not vary significantly over time. In conclusion, SCAP response is compromised when exposed to bacterial stimuli from infected dental root canals in anaerobic conditions. Thus, stem cell-mediated endodontic regenerative studies need to include microenvironmental conditions, such as the presence of microorganisms to promote further advantage in the field.
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Affiliation(s)
| | - Alexej Schmidt
- Department of Medical Biosciences, Pathology, Umeå University, Umeå, Sweden
| | - Maréne Landström
- Department of Medical Biosciences, Pathology, Umeå University, Umeå, Sweden
| | | | - Peyman Kelk
- Section for Anatomy, Department of Integrative Medical Biology, Umeå University, Umeå, Sweden
| | - Nelly Romani Vestman
- Department of Endodontics, County Council of Västerbotten, Umeå, Sweden.,Wallenberg Centre for Molecular Medicine, Umeå University, Umeå, Sweden
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5
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Blaser N, Backert S, Pachathundikandi SK. Immune Cell Signaling by Helicobacter pylori: Impact on Gastric Pathology. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2019; 1149:77-106. [PMID: 31049845 DOI: 10.1007/5584_2019_360] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Helicobacter pylori represents a highly successful colonizer of the human stomach. Infections with this Gram-negative bacterium can persist lifelong, and although in the majority of cases colonization is asymptomatic, it can trigger pathologies ranging from chronic gastritis and peptic ulceration to gastric cancer. The interaction of the bacteria with the human host modulates immune responses in different ways to enable bacterial survival and persistence. H. pylori uses various pathogenicity-associated factors such as VacA, NapA, CGT, GGT, lipopolysaccharide, peptidoglycan, heptose 1,7-bisphosphate, ADP-heptose, cholesterol glucosides, urease and a type IV secretion system for controlling immune signaling and cellular functions. It appears that H. pylori manipulates multiple extracellular immune receptors such as integrin-β2 (CD18), EGFR, CD74, CD300E, DC-SIGN, MINCLE, TRPM2, T-cell and Toll-like receptors as well as a number of intracellular receptors including NLRP3, NOD1, NOD2, TIFA and ALPK1. Consequently, downstream signaling pathways are hijacked, inducing tolerogenic dendritic cells, inhibiting effector T cell responses and changing the gastrointestinal microbiota. Here, we discuss in detail the interplay of bacterial factors with multiple immuno-regulatory cells and summarize the main immune evasion and persistence strategies employed by H. pylori.
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Affiliation(s)
- Nicole Blaser
- Department of Biology, Institute for Microbiology, Friedrich Alexander University Erlangen-Nuremberg, Erlangen, Germany
| | - Steffen Backert
- Department of Biology, Institute for Microbiology, Friedrich Alexander University Erlangen-Nuremberg, Erlangen, Germany
| | - Suneesh Kumar Pachathundikandi
- Department of Biology, Institute for Microbiology, Friedrich Alexander University Erlangen-Nuremberg, Erlangen, Germany.
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Rong J, Zhang L, Liao W, Xie Y, Lu N, Shu X. The Value of Confocal Laser Endoscopy in Assessing the Quality of Duodenal Ulcer Healing. Lasers Surg Med 2019; 51:701-708. [PMID: 31074497 DOI: 10.1002/lsm.23098] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/16/2019] [Indexed: 11/06/2022]
Abstract
BACKGROUND AND OBJECTIVE Confocal laser endomicroscopy (CLE) is a novel endoscopic technique that can image cells and subcellular layers of the gastric mucosa in vivo. We aimed to investigate the value of CLE in assessing the quality of ulcer healing (QOUH) and preliminarily establish evaluation criteria. MATERIALS AND METHODS Patients with duodenal ulcers were enrolled. After duodenal ulcer healing, we compared the value of CLE and white light endoscopy (WLE) in assessing the QOUH by using the histopathological diagnosis as the gold standard. At the same time, immunohistochemistry was performed to examine the expressions of transforming growth factor β1 (TGF-β1) and fibroblast growth factor 2 (FGF-2) in normal and scar tissues. RESULTS In assessing the QOUH classified as poor, good, and excellent by the pathological classification, the sensitivity of WLE was 57.14%, 50%, and 47.06%, the specificity was 87.80%, 52.38%, and 81.58%, and the accuracy was 80.00%, 50.91%, and 70.91%, respectively. Meanwhile, the sensitivity of CLE was 73.33%, 85.19%, and 92.31%, the specificity was 95%, 85.71%, and 92.86%, and the accuracy was 89.09%, 85.45%, and 92.73%, respectively. The κ value for the correlation with pathological diagnosis grade was 0.38 for WLE vs. 0.74 for CLE. The assessment of the QOUH in the CLE image classification showed great improvement compared with that in the WLE image classification. The image classification of CLE was not associated with the immunohistochemical expression of TGF-β1 or FGF-2 according the Spearman rank correlation (P > 0.05). CONCLUSION Compared with WLE, CLE has a higher value in assessing the QOUH. Lasers Surg. Med. © 2019 Wiley Periodicals, Inc.
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Affiliation(s)
- Jianfang Rong
- Department of Gastroenterology, The First Affiliated Hospital of Nanchang University, Nanchang, 330006 Jiangxi, China
| | - Liang Zhang
- Department of Medical, The First Affiliated Hospital of Jiangxi Medical College, Shangrao, 334000 Jiangxi, China
| | - Wangdi Liao
- Department of Gastroenterology, The First Affiliated Hospital of Nanchang University, Nanchang, 330006 Jiangxi, China
| | - Yong Xie
- Department of Gastroenterology, The First Affiliated Hospital of Nanchang University, Nanchang, 330006 Jiangxi, China
| | - Nonghua Lu
- Department of Gastroenterology, The First Affiliated Hospital of Nanchang University, Nanchang, 330006 Jiangxi, China
| | - Xu Shu
- Department of Gastroenterology, The First Affiliated Hospital of Nanchang University, Nanchang, 330006 Jiangxi, China
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7
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Arginase-1 and Treg Profile Appear to Modulate Inflammatory Process in Patients with Chronic Gastritis: IL-33 May Be the Alarm Cytokine in H. pylori-Positive Patients. Mediators Inflamm 2019; 2019:2536781. [PMID: 31320834 PMCID: PMC6610761 DOI: 10.1155/2019/2536781] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2018] [Revised: 02/20/2019] [Accepted: 04/16/2019] [Indexed: 02/07/2023] Open
Abstract
Helicobacter pylori (H. pylori) is a highly prevalent bacterium in our environment, directly involved in various upper digestive tract diseases, such as gastritis, peptic ulcer, and gastric cancer. Several molecules activating the immune system have been reported to be involved in containing H. pylori infection. This study is aimed at analyzing the mRNA expression of the cytokines IFN-γ, IL-17, IL-10, TGF-β, IL-6, IL-22, IL-23, and IL-33; transcription factors T-bet, RORC, and FOXP3; enzymes ARG1, ARG2, and NOS2; and neuropeptides VIP and TAC and their respective receptors VIPR1 and TACR1 in the stomach lining of patients with severe digestive disorders. One hundred and twenty six patients have been evaluated, presenting with symptoms in the upper digestive tract, with the clinical indication for an Upper Digestive Endoscopy exam. Two fragments of the mucosa of the gastric body and antrum have been collected for anatomopathological examination and to analyze the expression of enzymes, cytokines, and transcription factors using qPCR. Expression of the ARG1 gene was seen as significantly higher in the group of patients with chronic inactive gastritis than in the control group. Expression of the TGF-β gene and its FOXP3 transcription factor was significantly higher in the group of chronic inactive gastritis patients than in the control. Expression of IFN-γ, IL-17, IL-10, and TGF-β and the transcription factors, T-bet and RORC, in the presence or absence of H. pylori showed no significant difference. However, the expression of FOXP3 was significantly lower in H. pylori-positive patients than that in H. pylori-negative patients. ARG1 and Treg profile appeared to be modulating the inflammatory process, protecting patients from the tissue lesions with chronic inactive gastritis. Furthermore, we suggest that IL-33 may be a crucial mediator of the immune response against an infection, after gastric mucosal damage.
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Mechanisms of Inflammasome Signaling, microRNA Induction and Resolution of Inflammation by Helicobacter pylori. Curr Top Microbiol Immunol 2019; 421:267-302. [PMID: 31123893 DOI: 10.1007/978-3-030-15138-6_11] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Inflammasome-controlled transcription and subsequent cleavage-mediated activation of mature IL-1β and IL-18 cytokines exemplify a crucial innate immune mechanism to combat intruding pathogens. Helicobacter pylori represents a predominant persistent infection in humans, affecting approximately half of the population worldwide, and is associated with the development of chronic gastritis, peptic ulcer disease, and gastric cancer. Studies in knockout mice have demonstrated that the pro-inflammatory cytokine IL-1β plays a central role in gastric tumorigenesis. Infection by H. pylori was recently reported to stimulate the inflammasome both in cells of the mouse and human immune systems. Using mouse models and in vitro cultured cell systems, the bacterial pathogenicity factors and molecular mechanisms of inflammasome activation have been analyzed. On the one hand, it appears that H. pylori-stimulated IL-1β production is triggered by engagement of the immune receptors TLR2 and NLRP3, and caspase-1. On the other hand, microRNA hsa-miR-223-3p is induced by the bacteria, which controls the expression of NLRP3. This regulating effect by H. pylori on microRNA expression was also described for more than 60 additionally identified microRNAs, indicating a prominent role for inflammatory and other responses. Besides TLR2, TLR9 becomes activated by H. pylori DNA and further TLR10 stimulated by the bacteria induce the secretion of IL-8 and TNF, respectively. Interestingly, TLR-dependent pathways can accelerate both pro- and anti-inflammatory responses during H. pylori infection. Balancing from a pro-inflammation to anti-inflammation phenotype results in a reduction in immune attack, allowing H. pylori to persistently colonize and to survive in the gastric niche. In this chapter, we will pinpoint the role of H. pylori in TLR- and NLRP3 inflammasome-dependent signaling together with the differential functions of pro- and anti-inflammatory cytokines. Moreover, the impact of microRNAs on H. pylori-host interaction will be discussed, and its role in resolution of infection versus chronic infection, as well as in gastric disease development.
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Gang Liu Y, Teng YS, Cheng P, Kong H, Lv PY, Mao FY, Wu XL, Hao CJ, Chen W, Yang SM, Zhang JY, Peng LS, Wang TT, Han B, Ma Q, Zou QM, Zhuang AY. Abrogation of cathepsin C by
Helicobacter pylori
impairs neutrophil activation to promote gastric infection. FASEB J 2018; 33:5018-5033. [DOI: 10.1096/fj.201802016rr] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Affiliation(s)
- Yu Gang Liu
- Department of Microbiology and Biochemical PharmacyNational Engineering Research Centre of Immunological ProductsCollege of Pharmacy Chongqing China
| | - Yong Sheng Teng
- Department of Microbiology and Biochemical PharmacyNational Engineering Research Centre of Immunological ProductsCollege of Pharmacy Chongqing China
| | - Ping Cheng
- Department of Microbiology and Biochemical PharmacyNational Engineering Research Centre of Immunological ProductsCollege of Pharmacy Chongqing China
| | - Hui Kong
- Department of Microbiology and Biochemical PharmacyNational Engineering Research Centre of Immunological ProductsCollege of Pharmacy Chongqing China
| | - Pin Yi Lv
- Department of Microbiology and Biochemical PharmacyNational Engineering Research Centre of Immunological ProductsCollege of Pharmacy Chongqing China
| | - Fang Yuan Mao
- Department of Microbiology and Biochemical PharmacyNational Engineering Research Centre of Immunological ProductsCollege of Pharmacy Chongqing China
| | - Xiao Long Wu
- Department of Microbiology and Biochemical PharmacyNational Engineering Research Centre of Immunological ProductsCollege of Pharmacy Chongqing China
| | - Chuan Jie Hao
- Department of Microbiology and Biochemical PharmacyNational Engineering Research Centre of Immunological ProductsCollege of Pharmacy Chongqing China
| | - Weisan Chen
- La Trobe Institute of Molecular ScienceLa Trobe University Bundoora Victoria Australia
| | - Shi Ming Yang
- Department of GastroenterologyXinQiao HospitalThird Military Medical University Chongqing China
| | - Jin Yu Zhang
- Department of Microbiology and Biochemical PharmacyNational Engineering Research Centre of Immunological ProductsCollege of Pharmacy Chongqing China
| | - Liu Sheng Peng
- Department of Microbiology and Biochemical PharmacyNational Engineering Research Centre of Immunological ProductsCollege of Pharmacy Chongqing China
| | - Ting Ting Wang
- Department of Microbiology and Biochemical PharmacyNational Engineering Research Centre of Immunological ProductsCollege of Pharmacy Chongqing China
| | - Bin Han
- Department of PharmacyAffiliated Hospital of North Sichuan Medical College Nanchong China
| | - Qiang Ma
- Department of Clinical LaboratoryAffiliated Hospital of North Sichuan Medical College Nanchong China
| | - Quan Ming Zou
- Department of Microbiology and Biochemical PharmacyNational Engineering Research Centre of Immunological ProductsCollege of Pharmacy Chongqing China
| | - And Yuan Zhuang
- Department of Microbiology and Biochemical PharmacyNational Engineering Research Centre of Immunological ProductsCollege of Pharmacy Chongqing China
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10
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Lee HJ, Park JM, Hahm KB. [Role of Inhibitory Transforming Growth Factor-β Signal Smad7 in Helicobacter pylori-associated Gastric Damage]. THE KOREAN JOURNAL OF GASTROENTEROLOGY 2017; 68:186-194. [PMID: 27780942 DOI: 10.4166/kjg.2016.68.4.186] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
Background/Aims Transforming growth factor-beta (TGF-β) is a cytokine implicated in the susceptibility, development, and progression of gastrointestinal cancer and certain other neoplasms. In the later stages of cancer, TGF-β not only acts as a bystander of host-immune response, but also contributes to cell growth, invasion, and metastasis. In the current study, we generated gastric mucosal cells that stably express Smad7, and explored the Helicobacter pylori-associated biological changes between mock-transfected and Smad7-transfected RGM1 cells. Methods RGM1 cells stably transfected with Smad7 were infected with H. pylori, and molecular changes in apoptotic markers and inflammatory mediators were examined. Several candidate genes were explored in Smad7-overexpressing cells after H. pylori infection. Results Overexpression of Smad7 in RGM1 cells significantly increased the H. pylori-induced cytotoxicity compared to mock-transfected cells. Exaggerated increases in inflammatory mediators, cyclooxygenase 2, inducible NO synthase, and augmented apoptosis were noted in Smad7-overexpressing cells, whereas mitigated heme oxygenase 1 was noted in Smad7- overexpressing cells. These phenomena were reversed in cells transfected with Smad7 siRNA. Conclusions These data suggest that inhibition of Smad7 is a possible target for mitigating H. pylori-associated inflammation.
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Affiliation(s)
- Ho Jae Lee
- Department of Biochemistry, Gachon University School of Medicine, Incheon, Korea
| | - Jong Min Park
- CHA Cancer Prevention Research Center, CHA Bio Complex, CHA University, Seongnam, Korea
| | - Ki Baik Hahm
- CHA Cancer Prevention Research Center, CHA Bio Complex, CHA University, Seongnam, Korea.,Digestive Disease Center, CHA Bundang Medical Center, Seongnam, Korea
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11
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Butcher LD, den Hartog G, Ernst PB, Crowe SE. Oxidative Stress Resulting From Helicobacter pylori Infection Contributes to Gastric Carcinogenesis. Cell Mol Gastroenterol Hepatol 2017; 3:316-322. [PMID: 28462373 PMCID: PMC5404027 DOI: 10.1016/j.jcmgh.2017.02.002] [Citation(s) in RCA: 156] [Impact Index Per Article: 19.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/19/2016] [Accepted: 02/11/2017] [Indexed: 12/12/2022]
Abstract
Helicobacter pylori is a gram-negative, microaerophilic bacterium that infects the stomach and can lead to, among other disorders, the development of gastric cancer. The inability of the host to clear the infection results in a chronic inflammatory state with continued oxidative stress within the tissue. Reactive oxygen species and reactive nitrogen species produced by the immune and epithelial cells damage the host cells and can result in DNA damage. H pylori has evolved to evoke this damaging response while blunting the host's efforts to kill the bacteria. This long-lasting state with inflammation and oxidative stress can result in gastric carcinogenesis. Continued efforts to better understand the bacterium and the host response will serve to prevent or provide improved early diagnosis and treatment of gastric cancer.
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Key Words
- AP Endonuclease
- APE1, apurinic/apyrimidinic endonuclease 1
- BabA, blood group antigen binding adhesion
- CagA, cytotoxin-associated gene A
- DNA Damage
- Gastric Cancer
- H pylori
- IL, interleukin
- NADPH, nicotinamide adenine dinucleotide phosphate
- NapA, neutrophil activating factor A
- Nox, nicotinamide adenine dinucleotide phosphate oxidase
- O2-, superoxide
- OH, hydroxyl radical
- Oxidative Stress
- RNS, reactive nitrogen species
- ROS, reactive oxygen species
- TGF-β, transforming growth factor β
- VacA, vacuolating cytotoxin A
- iNOS, inducible nitric oxide synthase
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Affiliation(s)
- Lindsay D. Butcher
- Department of Medicine, University of California, San Diego, La Jolla, California
| | - Gerco den Hartog
- Department of Medicine, University of California, San Diego, La Jolla, California
| | - Peter B. Ernst
- Department of Pathology, University of California, San Diego, La Jolla, California
| | - Sheila E. Crowe
- Department of Medicine, University of California, San Diego, La Jolla, California
- Correspondence Address correspondence to: Sheila E. Crowe, MD, Department of Medicine, University of California, San Diego, 9500 Gilman Drive, La Jolla, California 92093-0063. fax: (858) 246-1788.Department of MedicineUniversity of CaliforniaSan Diego9500 Gilman DriveLa JollaCalifornia 92093-0063
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12
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Milk growth factors and expression of small intestinal growth factor receptors during the perinatal period in mice. Pediatr Res 2016; 80:759-765. [PMID: 27603563 DOI: 10.1038/pr.2016.150] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/12/2016] [Accepted: 05/26/2016] [Indexed: 01/23/2023]
Abstract
BACKGROUND Growth factors (GFs) are milk bioactive components contributing to the regulation of neonatal small intestinal maturation, and their receptors on the small intestinal epithelium play essential roles in mediating the functions of GFs. There is limited data correlating milk GFs and their receptors in the neonatal small intestine during the perinatal period. METHODS Small intestines of C57BL/6N mouse pups were collected at regular intervals during fetal life and up to postnatal day (PD) 60. Gene expression of GF receptors was determined by real-time qPCR. Milk GF concentrations up to PD21 were analyzed by enzyme-linked immunosorbent assay. RESULTS The majority of GF receptors showed significantly greater expression in the fetus than in postnatal life, and a sharp decrease occurred from PD14 extending to PD60; solid food restriction (PD14 and PD18) did not affect this decrease. Concentrations of five detected milk GFs demonstrated that GFs and the corresponding small intestinal receptors exhibited different correlations, with only milk transforming growth factor β1 (TGF-β1) having a significant positive correlation with TGF-β receptor 1 mRNA. CONCLUSION Gene expression of small intestinal GF receptors is likely a process of neonatal intestinal maturation that is affected concurrently by milk GFs and additional endogenous factors.
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Abstract
There have been few studies concerning the cytokine profiles in gastric mucosa of Helicobacter pylori-infected patients with normal mucosa, chronic gastritis, and gastric carcinoma (GAC).In the present study, we aimed to elucidate the genomic expression levels and immune pathological roles of cytokines-interferon (IFN)-γ, tumor necrosis factor (TNF)-α, interleukin (IL)-4, IL-6, IL-10, transforming growth factor (TGF)-β, IL-17A, IL-32-in H pylori-infected patients with normal gastric mucosa (NGM; control), chronic active gastritis (CAG), and GAC. Genomic expression levels of these cytokines were assayed by real-time PCR analysis in gastric biopsy specimens obtained from 93 patients.We found that the genomic expression levels of IFN-γ, TNF-α, IL-6, IL-10, IL-17A mRNA were increased in the CAG group and those of TNF-α, IL-6, IL-10, IL-17A, TGF-β mRNA were increased in the GAC group with reference to H pylori-infected NGM group.This study is on the interest of cytokine profiles in gastric mucosa among individuals with normal, gastritis, or GAC. Our findings suggest that the immune response of gastric mucosa to infection of H pylori differs from patient to patient. For individual therapy, levels of genomic expression of IL-6 or other cytokines may be tracked in patients.
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Affiliation(s)
- Derya Kivrak Salim
- From the Department of Medical Oncology (DKS), Faculty of Medicine, Akdeniz University, Antalya; Faculty of Health Sciences (MS), Kahramanmaras Sutcu Imam University, Kahramanmaras; Department of Microbiology (SK); and Department of Gastroenterology (HA, IS), Faculty of Medicine, Akdeniz University, Antalya, Turkey
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Komprda T, Sládek Z, Škultéty O, Křížková S, Rozíková V, Němcová B, Šustrová T, Valová M. Effect of dietarySchizochytriummicroalga oil on selected markers of low-grade inflammation in rats. J Anim Physiol Anim Nutr (Berl) 2016; 100:1169-1178. [DOI: 10.1111/jpn.12434] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2015] [Accepted: 10/08/2015] [Indexed: 12/13/2022]
Affiliation(s)
- T. Komprda
- Department of Food Technology; Mendel University in Brno; Brno Czech Republic
| | - Z. Sládek
- Department of Animal Morphology, Physiology and Genetics; Mendel University in Brno; Brno Czech Republic
| | - O. Škultéty
- Department of Animal Morphology, Physiology and Genetics; Mendel University in Brno; Brno Czech Republic
| | - S. Křížková
- Department of Chemistry and Biochemistry; Mendel University in Brno; Brno Czech Republic
| | - V. Rozíková
- Department of Food Technology; Mendel University in Brno; Brno Czech Republic
| | - B. Němcová
- Department of Food Technology; Mendel University in Brno; Brno Czech Republic
| | - T. Šustrová
- Department of Animal Morphology, Physiology and Genetics; Mendel University in Brno; Brno Czech Republic
| | - M. Valová
- Department of Food Technology; Mendel University in Brno; Brno Czech Republic
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Li N, Xie C, Lu NH. Transforming growth factor-β: an important mediator in Helicobacter pylori-associated pathogenesis. Front Cell Infect Microbiol 2015; 5:77. [PMID: 26583078 PMCID: PMC4632021 DOI: 10.3389/fcimb.2015.00077] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2015] [Accepted: 10/20/2015] [Indexed: 12/14/2022] Open
Abstract
Helicobacter pylori (H.pylori) is a Gram-negative, microaerophilic, helical bacillus that specifically colonizes the gastric mucosa. The interaction of virulence factors, host genetic factors, and environmental factors contributes to the pathogenesis of H. pylori-associated conditions, such as atrophic gastritis and intestinal metaplasia. Infection with H. pylori has recently been recognized as the strongest risk factor for gastric cancer. As a pleiotropic cytokine, transforming growth factor (TGF)-β regulates various biological processes, including cell cycle, proliferation, apoptosis, and metastasis. Recent studies have shed new light on the involvement of TGF-β signaling in the pathogenesis of H. pylori infection. This review focuses on the potential etiological roles of TGF-β in H. pylori-mediated gastric pathogenesis.
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Affiliation(s)
- Nianshuang Li
- Department of Gastroenterology, Institute of Digestive Disease, The First Affiliated Hospital of Nanchang University Nanchang, China
| | - Chuan Xie
- Department of Gastroenterology, Institute of Digestive Disease, The First Affiliated Hospital of Nanchang University Nanchang, China
| | - Nong-Hua Lu
- Department of Gastroenterology, Institute of Digestive Disease, The First Affiliated Hospital of Nanchang University Nanchang, China
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Shukla SK, Khatoon J, Prasad KN, Rai RP, Singh AK, Kumar S, Ghoshal UC, Krishnani N. Transforming growth factor beta 1 (TGF-β1) modulates Epstein-Barr virus reactivation in absence of Helicobacter pylori infection in patients with gastric cancer. Cytokine 2015; 77:176-9. [PMID: 26239415 DOI: 10.1016/j.cyto.2015.07.023] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2015] [Revised: 07/01/2015] [Accepted: 07/27/2015] [Indexed: 02/07/2023]
Abstract
BACKGROUND Transforming growth factor-beta 1 (TGF-β1), a multifunctional cytokine, acts as a key factor for Epstein-Barr virus (EBV) reactivation. We investigated the role of TGF-β1 in latent and lytic stages of EBV in relation to Helicobacter pylori infection among patients with gastric cancer (GC) and peptic ulcer disease (PUD). METHOD Gastric mucosal TGF-β1 expression was determined in 95 EBV positive patients with gastroduodenal pathology [GC 40, PUD 19 and non-ulcer dyspepsia (NUD) 36] by quantitative real time PCR. Presence of H. pylori infection was diagnosed when either culture or any two of three tests (RUT, histopathology and specific ureA PCR) were positive. Serum level of TGF-β1 was detected among 60 patients using ELISA. RESULTS Mucosal TGF-β1 mRNA expression was detected in 85 of 95 EBV positive patients and it was significantly higher in patients with GC (p=0.042). TGF-β1 expression tended to be higher among H. pylori non-infected than infected patients (3.80±6.24 vs. 2.07±2.50, p=0.085). Both mRNA and serum level had significant association with lytic stage of EBV in absence of H. pylori infection when compared with its presence (5.21±4.00 vs. 2.29±2.89, p=0.040 and 842.00 [669.55] vs. 662.63 [628.76], p=0.049; respectively). CONCLUSION TGF-β1 expression was significantly associated with GC. TGF-β1 was higher both at expression and translational levels in lytic EBV infection without H. pylori suggests that H. pylori infection might play important role in preventing EBV reactivation through attenuated TGF-β1 expression. This might be a "wise host defense against EBV reactivation".
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Affiliation(s)
- Sanket Kumar Shukla
- Department of Microbiology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, U.P. 226014, India; Department of Microbiology, University of Pennsylvania-School of Medicine, Philadelphia, PA 19104, United States
| | - Jahanarah Khatoon
- Department of Microbiology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, U.P. 226014, India
| | - Kashi Nath Prasad
- Department of Microbiology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, U.P. 226014, India.
| | - Ravi Prakash Rai
- Department of Microbiology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, U.P. 226014, India
| | - Aloukick Kumar Singh
- Department of Microbiology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, U.P. 226014, India
| | - Sushil Kumar
- Department of Gastroenterology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, U.P. 226014, India
| | - Uday Chand Ghoshal
- Department of Gastroenterology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, U.P. 226014, India
| | - Narendra Krishnani
- Department of Pathology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, U.P. 226014, India
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Nguyen TT, Kim SJ, Park JM, Hahm KB, Lee HJ. Repressed TGF-β signaling through CagA-Smad3 interaction as pathogenic mechanisms of Helicobacter pylori-associated gastritis. J Clin Biochem Nutr 2015; 57:113-20. [PMID: 26388668 PMCID: PMC4566024 DOI: 10.3164/jcbn.15-38] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2015] [Accepted: 03/23/2015] [Indexed: 12/19/2022] Open
Abstract
Helicobacter pylori (H. pylori) infection
causes chronic gastric inflammation, peptic ulceration, and gastric
carcinogenesis, in which H. pylori cytotoxin-associated gene A
(CagA) plays major pathogenic action. Since transforming growth factor-β
(TGF-β) and its signaling also are principally implicated in either
modulating gastric mucosal inflammatory responses or causing carcinogenesis and
are attenuated after H. pylori infection, we hypothesized that
dysregulated Smad signaling and repressed TGF-β might be core pathogenic
mechanism for H. pylori-associated gastritis or carcinogenesis.
Until now, no precise underlying mechanism how deranged TGF-β signaling
developed after H. pylori infection relevant to various
clinical manifestations remains unclear. In this study, we examined the
molecular mechanism about the inhibition of TGF-β signaling by H.
pylori CagA protein. H. pylori CagA significantly
suppressed TGF-β/Smad transcriptional responses through critical
inhibition of Smad3, though CagA interacted constitutively with Smad2, Smad3,
and Smad4. CagA inhibited TGF-β-induced suppression of proinflammatory
chemokines, such as IL-8, CXCL1 and CXCL3, as well as TGF-β-induced
transcription of target genes. In conclusion, repressed TGF-β signaling
associated with CagA-positive H. pylori infection could be an
important determinant for the outcome of H. pylori infection.
Therefore, TGF-β signaling is one of the important determinants to avoid
from H. pylori CagA pathogenicity.
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Affiliation(s)
- Thuy Trang Nguyen
- Laboratory of Chemoprevention, Lee Gil Ya Cancer and Diabetes Institute, Gachon University, Incheon 406-840, Korea
| | - Seong-Jin Kim
- CHA University Cancer Prevention Research Center, CHA Bio Complex, 335 Pangyo-ro, Gundang-gu, Seongnam 463-400, Korea
| | - Jong Min Park
- CHA University Cancer Prevention Research Center, CHA Bio Complex, 335 Pangyo-ro, Gundang-gu, Seongnam 463-400, Korea
| | - Ki Baik Hahm
- CHA University Cancer Prevention Research Center, CHA Bio Complex, 335 Pangyo-ro, Gundang-gu, Seongnam 463-400, Korea
| | - Ho-Jae Lee
- Laboratory of Chemoprevention, Lee Gil Ya Cancer and Diabetes Institute, Gachon University, Incheon 406-840, Korea
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Susceptibility to pediatric Helicobacter pylori infection correlates with the host responses of regulatory and effector T cells. Pediatr Infect Dis J 2014; 33:1277-82. [PMID: 25389709 DOI: 10.1097/inf.0000000000000464] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/03/2023]
Abstract
BACKGROUND Tolerance to the early acquisition of Helicobacter pylori is suggested because of a biased ratio of regulatory to effector T cells in a mice model. This study investigated whether the CD4CD25 regulatory T (Treg) and CD4+CD25- effector T (Teff) cell responses after H. pylori exposure determine H. pylori susceptibility in children. METHODS Treg and Teff cells from peripheral blood mononuclear cells (PBMCs) of H. pylori-infected and non-infected children were incubated with H. pylori protein. The cytokine levels and fraction of FOXP3+ to T cells were measured. FOXP3 expression was assessed by Western blotting and immunohistochemistry of gastric biopsies from dyspeptic children. RESULTS The fraction of FOXP3+ to CD4+CD25 high cells in PBMCs, FOXP3-positive staining and translation level in gastric tissues were higher in H. pylori-infected children than in controls (P < 0.05). The translation levels of TGF-β1 in gastric tissues were higher in H. pylori-infected children than in controls (P < 0.05). After H. pylori challenge, H. pylori-infected children had a positive net-change in TGF-β1 from Treg cells, and a negative net-change of IFN-γ from Teff cells. Paradoxically, the non-infected controls had a negative net-change in TGF-β1 from Treg cells, and a positive net-change of IFN-γ from Teff cells. CONCLUSIONS The host response of Treg cells with increases in FOXP3 and TGF-β1 combined with a reduction in IFN-γ by Teff cells may contribute to H. pylori susceptibility in children.
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Wang YQ, Li YM, Li X, Liu T, Liu XK, Zhang JQ, Guo JW, Guo LY, Qiao L. Hypermethylation of TGF-β1 gene promoter in gastric cancer. World J Gastroenterol 2013; 19:5557-5564. [PMID: 24023501 PMCID: PMC3761111 DOI: 10.3748/wjg.v19.i33.5557] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/11/2013] [Revised: 06/11/2013] [Accepted: 07/19/2013] [Indexed: 02/06/2023] Open
Abstract
AIM: To examine transforming growth factor-β1 (TGF-β1) promoter methylation in gastric cancer and to determine if Helicobacter pylori (H. pylori) or interleukin (IL)-1β could induce TGF-β1 hypermethylation in vitro.
METHODS: We examined the frequency and extent of TGF-β1 promoter methylation using methylation-specific PCR in the gastric tissues from 47 gastric cancer patients and 39 non-gastric cancer subjects. H. pylori infection was confirmed by a positive result from either a serological test, histological analysis or C13 urea breath test. GES-1 and MKN-45 cells co-cultured with H. pylori or treated with IL-1β for 12, 24 and 48 h in vitro tested the effects of H. pylori or IL-1β on TGF-β1.
RESULTS: Twenty-four/forty-seven (51%) cases of gastric cancer (GC) tissues showed TGF-β1 promoter methylation, 15/47 (31.9%) cases of matched non-cancerous gastric mucosa tissues from the GC patients, and 11/39 (28%) case of the normal gastric mucosa tissues from non-GC subjects showed TGF-β1 promoter methylation (51% vs 28%, P < 0.05). Significantly higher levels of methylation of TGF-β1 were found in the tumor tissues than in non-tumor tissues from GC patients (0.24 ± 0.06 vs 0.17 ± 0.04, P < 0.05) and normal gastric tissues from non-GC subjects (0.24 ± 0.06 vs 0.15 ± 0.03, P < 0.05). TGF-β1 methylation was found in 48.3% of H. pylori-positive gastric mucosal tissues whereas only 23.1% of H. pylori-negative gastric mucosal tissues showed TGF-β1 methylation (48.3% vs 23.1%, P < 0.05). IL-1β appeared to induce a dose-dependent methylation of TGF-β1 and the strongest methylation was observed in GES-1 cells treated with 2.5 ng/mL of IL-1β for 48 h. Further studies showed that pre-treatment of GES-1 cells with 20 ng/mL IL-1RA for 1 h could partially abolish the effect of IL-1β on TGF-β1 methylation. Infection of GES-1 cells by H. pylori was not found to induce significant TGF-β1 promoter methylation.
CONCLUSION: Our data revealed that TGF-β1 promoter is methylated in GC patients. IL-1β may be an important mediator for H. pylori induced gene methylation during GC development.
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Tüzün S, Yücel AF, Pergel A, Kemik AS, Kemik O. Lipid Peroxidation and Transforming Growth Factor-β1 Levels in Gastric Cancer at Pathologic Stages. Balkan Med J 2012; 29:273-6. [PMID: 25207013 DOI: 10.5152/balkanmedj.2012.026] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2012] [Accepted: 03/19/2012] [Indexed: 12/14/2022] Open
Abstract
OBJECTIVE High levels of TGF-β1 and enhanced TGF-β1 receptor signaling are related to the pathology of gastric cancer. This effect is caused by oxidative stress and lipid peroxidation products. The aim of this study was to investigate the levels of TGF-β1 and lipid peroxidation products in gastric cancer patients and their correlation with pathologic stage. MATERIAL AND METHODS Lipid peroxidation products and TGF-β1 levels were studied in the serum samples of 50 gastric cancer patients and 18 control subjects. RESULTS HNE-protein adducts and TGF-β1 levels were significantly higher in T2, T3 and T4 gastric cancers than in either the T1 stage or controls (p<0.001). Pathologic stage was correlated with TGF-β1 levels (r=0.702, p<0.05). CONCLUSION These markers production may contribute to tumor angiogenesis and aid in the prognosis of the gastric cancer.
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Affiliation(s)
- Sefa Tüzün
- Clinic of 2 Surgery Clinic, Haseki Training and Research Hospital, İstanbul, Turkey
| | - Ahmet Fikret Yücel
- Department of Surgery, Faculty of Medicine, Recep Tayyip Erdoğan University, Rize, Turkey
| | - Ahmet Pergel
- Department of Surgery, Faculty of Medicine, Recep Tayyip Erdoğan University, Rize, Turkey
| | - Ahu Sarbay Kemik
- Department of Biochemistry, Cerrahpaşa Faculty of Medicine, İstanbul University, İstanbul, Turkey
| | - Ozgür Kemik
- Department of Surgery, Faculty of Medicine, Yüzüncü Yıl University, Van, Turkey
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Role of gastric epithelial cell-derived transforming growth factor beta in reduced CD4+ T cell proliferation and development of regulatory T cells during Helicobacter pylori infection. Infect Immun 2011; 79:2737-45. [PMID: 21482686 DOI: 10.1128/iai.01146-10] [Citation(s) in RCA: 41] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
Gastric epithelial cells (GECs) express the class II major histocompatibility complex (MHC) and costimulatory molecules, enabling them to act as antigen-presenting cells (APCs) and affect local T cell responses. During Helicobacter pylori infection, GECs respond by releasing proinflammatory cytokines and by increasing the surface expression of immunologically relevant receptors, including class II MHC. The CD4(+) T cell response during H. pylori infection is skewed toward a Th1 response, but these cells remain hyporesponsive. Activated T cells show decreased proliferation during H. pylori infection, and CD4(+) CD25(+) FoxP3(+) regulatory T cells (Tregs) are present at the site of infection. In this study, we examined the mechanisms surrounding the CD4(+) T cell responses during H. pylori infection and found that transforming growth factor β (TGF-β) plays a major role in these responses. GECs produced TGF-β1 and TGF-β2 in response to infection. Activated CD4(+) T cells in culture with H. pylori-treated GECs were decreased in proliferation but increased upon neutralization of TGF-β. Naïve CD4(+) T cell development into Tregs was also enhanced in the presence of GEC-derived TGF-β. Herein, we demonstrate a role for GEC-produced TGF-β in the inhibition of CD4(+) T cell responses seen during H. pylori infection.
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